MEDICINAL CHEMISTRY

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g. Binding to zinc through either a carboxylate or phosphinate mimics the peptide hydrolysis transition state. h. Esterification of the carboxylate or phosphinate produces an orally bioavailable prodrug. i. X is usually methyl to mimic the side chain of alanine. Within the dicarboxylate series, when X equals n-butylamine (lysine side chain) this produces a compound, which is orally active without being a prodrug. j. Optimum activity occurs when stereochemistry of inhibitor is consistent with L-amino acid stereochemistry. Analogous values for these functional groups in lisinopril are 3.3 and 1.7. The enalaprilat and lisinopril, all of the compounds possess good lipid solubility. Compounds which contain hydrophobic bicyclic ring systems are more lipid soluble than those which contain proline. A comparison of the log P values of benazepril, perindopril, quinapril, ramipril, and trandolapril to those for captopril and enalapril illustrates this fact. As previously discussed, enalaprilat is much more hydrophilic than its ester prodrug and is currently the only ACE inhibitor marked for intravenous administration. In terms of solubility, lisinopril is probably the most interesting compound in that it is the most hydrophilic inhibitor, yet unlike enalaprilat, it is orally active. One possible explanation for this phenomenon is that in the duodenum, lisinopril will exist as a di-zwitterion in which the ionized groups can internally bind to one another. In this manner, lisinopril may be able to pass through the lipid bilayer with an overall net neutral charge. Structure-activity Relationships of angiotensin II antagonists: All commercially available angiotensin II antagonists are analogs of the following general structure: 1) The "acidic group" is thought to mimic either the Tyr4 phenol or the A-sp, carboxylate of angiotensin II.Groups capable of such a role include the carboxylic acid (A), a phenyl tetrazole (B), or a phenyl carboxylate (C). 2) In the biphenyl series, the tetrazole and carboxylate groups must be in the ortho position for optimal activity (the tetrazole group is superior in terms of metabolic stability, lipophilicity, and oral bioavailability). 3) The n-butyl group of the model compound provides hydrophobic binding and most likely mimics the side chain of Ile5, of angiotensin II. As seen with candesartan and telmisartan, this n-butyl group can be replaced with a substituted benzimidazole ring. 4) The imidazole ring, or an isosteric equivalent, is required to mimic the His,, side chain of angiotensin II. 5) Substitution with a variety of R groups including a carboxylic acid, methyl alcohol, ether, or an alkyl chain is required to mimic the Phe, of angiotensin II. All of these groups are thought to interact with the AT, receptor, some through ionic or ion-dipole bonds and others through hydrophobic interactions.
N N R Acidic group (102) Acidic group: CO 2H A HN N N N HOOC B C (103) (104) Structure activity Relationships of calcium channel blockers: The structure-activity relationships for 1, 4-DHP derivatives indicate that the following structural features are important for activity: 1) A substituted phenyl ring at the C4, position optimizes activity (heteroaromatic rings, such as pyridine, produce similar therapeutic effects; but are not used due to observed animal toxicity). C4 substitution with a small nonplanar alkyl or cycloalkyl group de creases activity. R 1 R 2 X 6 5 H N 1 4 3 CH 3 2 Key to general structure:(105) R 3 (CH3) 2CHO 2C Isradipine: (18) H 3C H N CH 3 CO 2CH 3 Table: Structures of the Dihydropyridine Calcium Channel Blockers Compounds R1 R2 R3 X Amlodipine CH2OH2CH2NH2 CO2CH2CH3 CO2CH3 2-Cl 2-Felodipine CH3 CO2CH2CH3 CO2CH3 2,3-Cl2 Nicardipine CH3 CO2(CH2)2-NH(Me)CH2-Ph CO2CH3 3-NO2 Nifedipine CH3 CO2CH2CH3 CO2CH3 2-NO2 Nimodipine CH3 CO2CH2 CH2OCH3 CO2CH(CH3)2 3-NO2 Nisoldipine CH CO2CH2CH( CH3)2 CO2CH3 2-NO2 N N O
Page 1 and 2: CONTENTS Antianginal Drugs Anticoag
Page 3 and 4: c) Dihydropyridine derivative: e.g.
Page 5 and 6: 2 (d) 4. H 3C H 3C HO CH-CH 2-O-CH
Page 7 and 8: pentaerythritol, and is supplied di
Page 9 and 10: of' streptokinase, urokinase and ti
Page 11 and 12: Low-molecular-weight Heparins, B.P.
Page 13 and 14: OH COOCH 3 AC 2O Methyl salicylate
Page 15 and 16: Warfarin and other coumarin derivat
Page 17 and 18: Structure-activity Relationship All
Page 19 and 20: Mean Arterial Blood Pressure (MABP)
Page 21 and 22: Table-1 ---------------------------
Page 23 and 24: Ramipril Altace ( Hoechst-Marion) 2
Page 25 and 26: Official drugs: Prazosin Hydrochlor
Page 27 and 28: treatment of hypertension, the dosa
Page 29 and 30: NH ClCH 2CN NCH 2CN Perhydroazocine
Page 31 and 32: B (2). Angiotensin Receptor Antagon
Page 33 and 34: CH3COOC2H5 Diazoxide (90) Cl NH 2 S
Page 35: Structure-activity Relationships of
Page 39 and 40: Structure-activity Relationships of
Page 41 and 42: HO HO HO HO H 3C CH 3 H Digitoxigen
Page 43 and 44: efractory periods. These are mainly
Page 45 and 46: Structure - Activity Relationship:
Page 47 and 48: Hydralazine is a direct relaxant of
Page 49 and 50: K4[Fe(CN) 6].3H2O + 6HNO3 H2[(NO)Fe
Page 51 and 52: conduction velocity, and decrease s
Page 53 and 54: Synthesis of Moricizine: (153) H N
Page 55 and 56: Tocainide Hydrochloride (±)-2-Amin
Page 57 and 58: influx through β-receptor blockade
Page 59 and 60: Cl Cl CH2CH=CH2 N N N H Alinidine (
Page 61 and 62: (iii) Intermediate density lipoprot
Page 63 and 64: Structure-activity Relationship Mev
Page 65 and 66: to the bile acids. Thus due to ente
Page 67 and 68: moderate reduction in cholesterol l
Page 69 and 70: (iii) Other types: (a) Insulin rece
Page 71 and 72: non-crystalline insulin as far as o
Page 73 and 74: for better drug in this series. Sub
Page 75 and 76: Key to general structure X SO 2 NH
Page 77 and 78: Official Drugs: Insulin, B.P. It is

MEDICINAL CHEMISTRY

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